Project Summary Addiction is a chronic, relapsing disorder with few effective therapies. Following drug withdrawal, addicted patients experience a persistent drive to seek drugs, which is driven in part by the emergence of a negative affective state. Therapeutic strategies that could reduce this negative affective state may reduce drive for drug seeking and help prevent relapse. Two features of the withdrawal-associated negative affective state are impaired hedonic valuation of and motivation for non-drug rewards. These have both been causally linked to GABAergic and opioid-dependent interactions between the nucleus accumbens (NAc) and ventral pallidum (VP). Following withdrawal from cocaine, GABAergic transmission between the NAc and VP is weakened. This plasticity is mediated by endogenous opioids and has been causally implicated in motivational changes, hedonic valuation and cocaine seeking after withdrawal by optogenetic normalization of transmission. Since optogenetic manipulations are not applicable in clinical settings, we propose to investigate whether we can use deep brain stimulation (DBS; a surgical therapy whereby current is passed through electrodes implanted in specific brain nuclei) to restore NAc to VP transmission following cocaine withdrawal. We will first test the hypothesis that DBS in the VP can normalize transmission at NAc to VP synapses following withdrawal from cocaine self-administration. We will then test the hypothesis that DBS in the VP increases motivation for natural rewards following cocaine withdrawal. High-frequency DBS has been tested in the NAc for the treatment of addiction, although the effects have been inconsistent. Our proposal aims to improve on this approach by designing a protocol that works through well-defined synaptic mechanisms to restore circuit function after cocaine withdrawal. Moreover, understanding the principles of DBS action may have implications for treating other neuropsychiatric conditions accompanied by negative affect, such as depression or bipolar disorder.